Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change

Abstract

Multiple cancers may arise from within a clonal region of preneoplastic epithelium, a phenomenon termed 'field change'. However, it is not known how field change develops. Here we investigate this question using lineage tracing to track the behaviour of scattered single oesophageal epithelial progenitor cells expressing a mutation that inhibits the Notch signalling pathway. Notch is frequently subject to inactivating mutation in squamous cancers. Quantitative analysis reveals that cell divisions that produce two differentiated daughters are absent from mutant progenitors. As a result, mutant clones are no longer lost by differentiation and become functionally immortal. Furthermore, mutant cells promote the differentiation of neighbouring wild-type cells, which are then lost from the tissue. These effects lead to clonal expansion, with mutant cells eventually replacing the entire epithelium. Notch inhibition in progenitors carrying p53 stabilizing mutations creates large confluent regions of doubly mutant epithelium. Field change is thus a consequence of imbalanced differentiation in individual progenitor cells.

Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration

“…Six days after wounding, we observed that GFP C cells from K14;dnMAML mice displayed a strong bias toward occupying the basal layer of the wound, whereas YFP C cells from control animals were more frequently observed suprabasally, similar to results recently reported in esophageal epithelium 29 (Fig. 4D).…”

Mutation, clonal fitness and field change in epithelial carcinogenesis

“…Surprisingly, the Maml1 mutant mice do not develop tumours and oesophageal integrity is preserved. This can be attributed to the fact that once the mutant cells have colonized the epithelium, the cells become crowded and the symmetric differentiation division outcome is restored [49]. The ability of the epithelium to establish a new 'steady state' by normalizing the probability of differentiation suggests a robust mechanism to defend the tissue against aggressive mutations.…”

“…Expression of DNMaml1 in scattered oesophageal progenitors both accelerates their proliferation and abolishes cell divisions that result in two differentiated cells. As well as imbalancing cell production in favour of proliferating cells, this also blocks clone loss by differentiation, rendering the DNMaml1 clones functionally 'immortal' [49]. In addition, the mutant cells actively drive out their wild-type neighbours by increasing the probability of differentiation of wild-type cells bordering the clone.…”

“…Inactivating mutations of the Notch pathway are very common in squamous carcinomas [45][46][47][48]. Lineage tracing of Notch inhibited clones has been modelled by expressing a dominant negative mutant of the Maml1 gene (DNMaml1) fused to a fluorescent protein to allow lineage tracing in transgenic mice [49]. Expression of DNMaml1 in scattered oesophageal progenitors both accelerates their proliferation and abolishes cell divisions that result in two differentiated cells.…”

Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells

“…In the esophagus, however, Notch inactivation appears to promote proliferation and basal layer crowding, but not tumor formation or inflammation (Alcolea et al 2014). Not only does Notch inactivation cause sufficient proliferation to regenerate an entire esophageal epithelium, but it also induces proliferation in adjacent cells containing normal Notch signaling (Alcolea et al 2014).…”